pH-Sensitive Immolative Polymer for Nucleic Acid Delivery
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Solution Overview
Problem
There is a need for new materials and strategies that enable or enhance the delivery of therapeutic agents, diagnostic probes, and research tools across the plasma membrane of cells and other biological barriers, particularly for clinical, diagnostic, and research applications involving nucleic acids.
Innovation Solution
A cell-penetrating complex is provided, comprising a nucleic acid non-covalently bound to a cationic amphipathic polymer with a pH-sensitive immolation domain, as well as a nanoparticle composition comprising multiple such complexes. The cationic amphipathic polymer is formulated in specific structures to facilitate the transport of nucleic acids across cellular membranes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If nucleic acids are delivered across the plasma membrane using conventional methods, then delivery efficiency is low, but using cationic amphipathic polymers improves delivery efficiency while potentially causing increased toxicity
Solution Approach 1:
The polymer structure incorporates pH-sensitive immolation domains that change conformation or charge state in response to pH variations between extracellular and intracellular environments. This parameter change enables the polymer to maintain high delivery efficiency while reducing toxicity by becoming less cationic or more hydrophobic in the neutral pH of extracellular space compared to the acidic pH of endosomes
Solution Approach 2:
The cationic amphipathic polymer combines multiple functional domains within a single molecular structure: cationic regions for nucleic acid binding and membrane interaction, amphipathic regions for membrane disruption and endosomal escape, and pH-sensitive immolation domains for controlled release. This composite structure achieves high delivery efficiency while mitigating toxicity through the cooperative function of its diverse components
2Reliability
If pH-sensitive immolation domains are incorporated into the polymer, then controlled release and endosomal escape are improved, but polymer structure complexity increases
Solution Approach 1:
The polymer is divided into distinct functional segments or domains: cationic regions for nucleic acid binding, amphipathic regions for membrane interaction, and pH-sensitive immolation domains for controlled release. This segmentation allows each domain to perform its specific function independently while contributing to the overall reliability of controlled release and endosomal escape
Solution Approach 2:
The pH-sensitive immolation domains undergo parameter changes (conformational changes, charge changes, or solubility changes) in response to pH variations. This enables the polymer to automatically trigger controlled release and endosomal escape in response to the pH gradient between extracellular space and endosomes, improving reliability without requiring complex external control mechanisms
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The described solutions effectively facilitate the transfection of nucleic acids into cells, inducing an immune response and demonstrating potential in vaccination strategies, cancer immunotherapy, protein therapy, and gene editing applications.
Implementation Method 1
a nucleic acid non-covalently bound to a cationic amphipathic polymer
Implementation Method 2
the cationic amphipathic polymer including a pH-sensitive immolation domain
Data Source
AI summary
There are provided herein, inter alia, complexes, compositions and methods for the delivery of nucleic acid into a cell in vivo. The complexes, compositions and methods may facilitate complexation, protection, delivery and release of oligonucleotides and polyanionic cargos into target cells, tissues, and organs both in vitro and in vivo.